Carney complex (CNC) is an autosomal dominant disorder in which cardiac myxomas (the most common primary cardiac tumor) occur in the setting of spotty pigmentation of the skin, extracardiac myxomas, rare nonmyxomatous tumors, and endocrinopathy. We have shown that haploinsufficient mutations of the PRKAR1A gene encoding the R1a regulatory subunit of cAMP-dependent protein kinase A cause ~2/3 of CNC. Moreover, our prkar1a +/- mouse knockout replicates several aspects of CNC including male infertility and tumorigenesis. Both murine phenotypes are rescued by genetic ablation of the Ca PKA catalytic subunit, and similar genetic modifiers may alter human tumorigenesis. We also showed that mutation of the MYH8 gene encoding perinatal myosin causes a CNC variant in which familial cardiac myxomas, spotty skin pigmentation, and endocrinopathy occur in the setting of limb contracture. The pathways in which PRKAR1A and MYH8 could intersect or synergize to contribute to heart development and to tumorigenesis remain to be established. We hypothesize that the MYH8 and PRKAR1A genes act at different stages of a molecular and cell biologic pathway to tumorigenesis. MYH8 mutations may promote the persistence into adulthood of embryonic cells that can act as tumor progenitors while PRKAR1A mutations altering the adult intracellular signal transduction milieu to stimulate the tumorigenic expansion of these progenitors. Therefore, we propose: [1] To determine requirements for perinatal myosin during cardiogenesis and tumorigenesis, [2] To determine if PRKAR1 A-dependent tumorigenesis is mediated through increased PKA activity, and [3] To identify novel genes in whom mutations cause human CNC. To achieve these aims, we will use genetically engineered chick and mouse models to determine how prkar1a, Myh8, and other genetic modifiers can regulate myogenesis, heart development and tumorigenesis. In addition, we will study the action of these genes in the myofibroblast population to determine the contribution of this lineage to CNC. Finally, we will also identify novel CNC disease genes to define additional pathogenic mechanisms intersecting with PRKAR1A and MYH8. Our research will highlight not only potential targets for treatment of cardiac myxomas and other CNC tumors but also will shed light on fundamental mechanisms regulating cell differentiation and growth that will promote improved treatments for a variety of common cardiomyopathies.